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An efficient method for N-formylation of amines using natural HEU zeolite at room temperature under solvent-free conditions Bahari, Siavash ; Mohammadi-Aghdam, Babak ; Mohammad Sajadi, S. ; Zeidali, Fereshteh

RNHR' + HCOOH HEU zeolite (cat)room temp.; solvent-free

N

R' R

CHO

R = aryl, alkylR' = aryl, alkyl, H

Leave this area blank for abstract info.

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An efficient method for N-formylation of amines using natural HEU zeolite at room temperature under solvent-free conditions

Siavash Baharia, Babak Mohammadi-Aghdam*a, S. Mohammad Sajadib, Fereshteh Zeidalia aDepartment of Chemistry, Islamic Azad University, Aliabad Katool Branch, Aliabad Katool, Iran bDepartment of , Faculty of Science, Soran University, Soran, Kurdistan Regional Government, 624, Iraq

Abstract—A rapid and practical green route for N-formylation of amines with formic acid at room temperature using HEU zeolite as a heterogeneous, reusable and highly efficient catalyst is described. The process is remarkably simple and environmentally benign. © 2014 Elsevier Science. All rights reserved

Formamides are important intermediates in the preparation of amine derivatives and have been widely used in the synthesis of pharmaceutically valuable compounds.1,2 Formamides serve as very useful reagents in Vilsmeier formylation and in the synthesis of formamidines and isocyanides.3 Moreover, formamides are Lewis bases, which are used as catalysts in reactions such as allylation, synthesis of acid chlorides from carboxylic acids, and hydrosilylation of carbonyl compounds.4 In addition, the formyl group is an important amine-protecting group in peptide synthesis.5

Several methods have been reported in the literature for the N-formylation of amines. Acetic formic anhydride6 is a well known formylating reagent, but is sensitive to moisture and cannot be stored due to decomposition to acetic acid and carbon monoxide. Formylation using chloral,7 activated formic acid in the presence of DCC8 or EDCI,9 activated formic esters,10 ammonium formate in acetonitrile,11 2,2,2-trifluoroethyl formate,12 ZnO13 and polyethylene glycol14 have been used for this purpose.

However, there are several factors in some of these methods which limited their applications. In many of these methods, the applicable reagents are toxic, expensive or out of accessible. Also, most of the other N-formylation methods have disadvantages such as long reaction times, formation of side products and thermal instability. Recently, Das et al.14 reported a useful method for N-formylation of anilines at room temperature by using formic acid in polyethylene glycol (PEG-400); however, the success of this method is limited only to aromatic primary amines, and the method does not avoid the use of organic solvent. Recently the formylation using ZnCl2, FeCl3, AlCl3, and NiCl2 has been reported.15 They observed no reaction when a mixture of formic acid and aniline was heated at 100 oC for 4 h in the absence of Lewis acid. Aqueous formic acid (85%) has previously been reported as

a formylating agent under conventional heating. However, this method needs a Dean-Stark trap under reflux conditions in toluene and involves long reaction times.16 Also, the formylation of anilines having electron-withdrawing groups was found to be difficult.16 Very recently, Heydari and co-workers reported N-formylation of amines using sulfonic acid supported hydroxyapatite encapsulated γ-Fe2O3.17 Despite the usefulness of this method, such as high yields and mild conditions, there are difficulties in the preparation of catalyst and availability of reagents. Furthermore HCl evolution occurs during the preparation of catalyst. Therefore, the pursuit of more convenient and practical synthetic methods for these compounds still remains an active research area.

The use of heterogeneous catalysts in different areas of organic synthesis has now reached significant levels, not only because it enables environmentally benign synthesis, but also due to the good yields, accompanied by excellent selectivities, that can frequently be achieved.18 Zeolites are uniform microporous crystalline materials and have been investigated extensively and applied as solid catalysts in the field of petrochemistry.19 Zeolites are also known to catalyze various synthetic organic transformations much more effectively and selectively than the Lewis acid catalysts.20

Herein we report the N-formylation of amines using formic acid in the presence of a catalytic amount of zeolite HEU20b at room temperature under solventless conditions in high yields, which can be reused without any loss of activity (Scheme 1).

Scheme 1.

A variety of primary and secondary amines (aromatic, aliphatic and heterocyclic) was treated with formic acid in the presence of HEU zeolite as the catalyst to give the

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corresponding N-formyl amines in good to excellent yields (Table 1). Anilines bearing both electron-donating and electron-withdrawing functionalities were also found to undergo the conversion in a facile manner with excellent yields. In our experimental procedure, no isolable side product has been observed. Several sensitive functionalities such as -OH and halogen (Cl, Br) were unaffected under the present reaction conditions. The open chain aliphatic amines reacted smoothly under such reaction conditions; even benzylamine that was previously reported to provide low yield21 (42%) furnished good yield (93%) following this reaction protocol (Table 1, entry 2). Previously, the N-formylation of 4-nitroaniline was found to be difficult.16 It is well known that the amino group in 4-nitroaniline is of very low basicity and hence not easily acylated. In contrast with previously methods, the method can be applied to conversion of poorly reactive 4-nitroaniline (Table 1, entry 12).

In comparison with the primary amines, secondary amines need longer reaction times (Table 1). Thus excellent chemoselectivity was observed for the conversion of primary amines in the presence of secondary amines, as shown in Scheme 2.

Scheme 1.

O-Formylation of phenols did not take place. It was found that this reaction is chemoselective, and only N-formylation product was formed with molecules containing both the hydroxyl and the amino group. Thus, the aminophenols furnished only the N-formylation products under the present reaction conditions (entries 5, 6 and 20).

Zeolite catalysts with their supercages and channels of defined sizes, have received considerable attention in the last decade for organic transformations, e.g. in the synthesis of intermediates and the petrochemical industry. Natural HEU zeolite was characterized by X-ray powder diffraction and SEM technique. The composition of HEU (Si/Al = 5.0) zeolite used is CaAl2Si7O18·6H2O and was obtained from Semnan province, Iran.20b The crystal size of catalyst was determined to be below 3 µm using SEM technique.

To show the merits of HEU zeolite in comparison with other reported catalysts, we summarized some of results for N-formylation of benzylamine in Table 2, which shows that HEU zeolite is an equally or more efficient catalyst with respect to reaction time and yield than previously reported ones.

HEU was used in a recycle experiment; after each cycle the catalyst was filtered off and reused in the next cycle without any post-treatment. The catalyst shows good activity even after five cycles (Table 1, entry 1).

In conclusion, we have developed a novel and highly efficient solvent-free protocol for N-formylation of amines using nontoxic, inexpensive, and natural HEU zeolite. Operational simplicity, short reaction times, the possibility for reusing the catalyst, chemoselectivity, solvent-free

media, very mild reaction conditions, environmentally friendly reaction conditions, the compatibility with various functional groups are the advantages of the present procedure. No methodology has been reported so far where only formic acid is used as the sole formylating agent without any solvent in the presence of natural catalyst. We believe that this will present a better and more practical alternative to the existing methodologies for the N-formylation of amines.

General experimental procedure for N-formylation of amines

To a solution of amine (1.0 mmol) and aq. formic acid (1.2 mmol) was added HEU zeolite (0.05 g) and the reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC (see Table 1). The reaction mixture was then separated by an external magnet and the catalyst was washed and dried to reuse in the next run. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to obtain the spectra-pure compounds.

N-Phenyl formamide (Table 1, entry 1): 1H NMR (400 MHz, CDCl3) δ 9.38 (brs, 1H, trans), 8.99 (brs, 1H, cis), 8.66 (d, 1H, J = 11.3, trans), 8.29 (s, 1H, cis), 7.12-7.61 (m, 5H, Ar-H).

N-Formylpiperidine (Table 1, entry 17): B.p. 92-95 °C; 1H NMR (400 MHz, CDCl3) δ 1.81-1.86 (m, 4H), 3.50 (t, 2H), 3.52 (t, 2H), 8.23 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 25.65, 25.89, 41.66, 46.89, 162.52.

N-Methyl-N-formylaniline (Table 1, entry 18): 1H NMR (400 MHz, DMSO-d6) δ 3.23 (s, 3H), 7.25-7.47 (m, 5H), 8.55 (s, 1H,).

Acknowledgments

We are thankful to the Islamic Azad University, Ali Abad Katool Branch and University of Salahaddin for the partial support of this research

References

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RNHR' + HCOOH HEU zeolite (cat)room temp.; solvent-free

N

R' R

CHO

R = aryl, alkylR' = aryl, alkyl, H

Scheme 1.

+HEU zeolite (cat)

room temp.; solvent-free

NH2 NHPh

HCOOH (1eq.)

30 min

+

NHCHO NPhOHC

0 %91 %1 eq. 1 eq. Scheme 2.

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Table 1. N-Formylation of amines using HEU zeolite in formic acid at room temperature under solvent-free conditions

Entry Amine Product Reaction time (min) Isolated yield (%) Ref.a

1

30 91, 88b 22, 27

2

35 93 22, 27

3 NH2H3C

NHCHOH3C

30 90 22, 27

4 NH2H3CO

NHCHOH3CO

25 91 22

5

35 87 22

6 NH2HO

NHCHOHO

40 86 22, 27

7

20 88 22, 27

8

NH2

Cl

NHCHO

Cl

30 93 22

9 NH2Cl

20 88 22

10

25 93 13

11 NH2

O2N

NHCHO

O2N

25 90 22

12

30 89 22, 27

13

30 88 13, 22

14 OH

No reaction - - -

15

No reaction - - -

16

35 73 22, 27

17

N

H

N

CHO

50 76 This work

18 NHCH3

CHON CH3

50 82 22

19 HN

CHON

70 74 22, 27

20 HOCH2CH2NH2 HOCH2CH2NHCHO 40 75 22

21 H3C(CH2)3NH2 H3C(CH2)3NHCHO 35 78 22 aReported in the literature. bYield after the fifth cycle.

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Table 2. Comparison HEU zeolite with reported catalysts in the N-formylation of benzylamine

Entry Formylating method Solvent Temperature Reaction time Yield (%) Ref.

1 2 3 4 5 6 7 8 9 10 11

HCOOH, Sodium formate HCOOH, Anhydrous ZnCl2 Methylformate Ammonium formate HCOOH, PEG HCOOH, H2O2, Copper salt HCOOH, Amberlite IR-120 HC(OEt)3 HCOOH γ-Fe2O3

@ HAp-SO3H HCOOH, HEU zeolite

Solvent-free Solvent-free PhMe CH3CN Solvent-free MeOH Solvent-free H2O Solvent-free Solvent-free Solvent-free

Room temperature 70 oC Room temperature Reflux Room temperature Room temperature Microwave, 320 W Microwave, 90 oC 80 oC Room temperature Room temperature

2.5 h 90 min 2 h 6 h 6 h 75 min 95 min 2 h 60 min 40 min 35 min

85 90 94 88 42 80 92 78 90 92 93

22 15 23 11 14 24 25 26 27 17 This work